Radiation bystander effects

Los Alamos National Laboratory biologist Bruce Lehnert's study of the
effects of extracellular mediators, including proteins, from irradiated
human cells on non-irradiated cells has confirmed the existence of the
so-called "bystander effect," which essentially refers to radiation-
induced effects in unirradiated cells.

The effect induces a response that could hold the key to the causes
of gene instability that underly cancer, as well as other phenomena
such as increases in cell growth that have been observed with low
doses of ionizing radiation, radio-adaptive responses to low doses of
radiation provide protection against the killing effects of subsequent
high-dose exposure.

"We are studying cancer mechanisms at their most basic level, looking
for pathways that may underlie genomic instability," Lehnert said.
"Finding those pathways may show us how we can deal therapeuti-
cally with the health effects of radiation exposure."

According to Lehnert, mounting evidence suggests that many impor-
tant effects of radiation can occur in the absence of direct irradiation
of cell nuclei. Results from recent experiments show that at least
some cancer-associated effects of ionizing radiation, including the induction of genetic mutations, can occur in cells that have
not been directly exposed to radiation.These results have
profound implications for assessing cancer risk and other collateral
effects of environmental, diagnostic or therapeutic exposure to
ionizing radiation.

When Lehnert first came to Los Alamos nearly 20 years ago, he
worked on the effects of toxic gases on the lungs and lung defense
mechanisms. On the lookout for interesting problems in radiation
biology, Lehnert was intrigued by papers on genomic instability that
suggested a far-reaching phenomenon activates something in cells
making them susceptible to damage even when their nuclei are not
directly irradiated.

Recent advances in charged-particle micro-beam technology have
provided a means to directly assess the consequences of irradiating cell
nuclei as opposed to irradiating extranuclear regions. With these
approaches, the nucleus and the cell's body, or cytoplasm, are differen-
tially stained with compounds that fluoresce with different emission
spectra when illuminated by ultraviolet light. This allows visualization
of the subcellular regions so that the subcompartments can be prefer-
entially targeted for irradiation by charged particles and the results
observed. Such studies have confirmed that the irradiation of parts of
cells aside from their nuclei can cause numerous effects.

Lehnert and his group obtained evidence that alpha particles like those
emitted by radon, radon progeny and plutonium 238 can cause
increases in sister chromatid exchanges – an indicator of DNA damage
that involves symmetrical transfers of DNA fragments between two
chromatids of the same chromosome – in normal human cells without
direct nuclear traversals. They
also found that these increases
were maximally induced over
a low-dose range in an "all
or none " manner. They
concluded that the excessive
chromatid exchange response
could have been induced by
an effect of alpha particles in
some region outside the
nucleus and theoretically even
outside the cell itself.

In further investigations, Lehnert's group found unequivocal evidence
that this and several other cellular effects are mediated by the production
of extracellular factors that transmit signals that produce responses in
unirradiated cells to the same extent as those observed when cells are
directly irradiated to low doses of radiation.

Definitively demonstrating that radiation can produce bystander effects
on neighboring cells has introduced a new variable in risk assessment.
Under some experimental conditions, DNA, or even whole cells, can no
longer be viewed as the only relevant target for the actions of ionizing
radiation, or even necessarily the most important target for eliciting at
least some of the detrimental effects of ionizing radiation.

The Department of Energy has long been interested in individualized
risk assessment for radiation exposure. Scientists are seeking to identify
genes that play crucial roles in determining an individual's susceptibility to the effects of ionizing
radiation and are looking for the mechanism that causes genes to become unstable. What is clear
from Lehnert's work is that one important bystander effect is an increase in intracellular reactive
oxygen species, which potentially can cause several types of DNA damage. A second important
bystander effect is that the growth of cells is enhanced, and cells showing this response fail to stop
growing when subsequently exposed to radiation.

"All of these features of bystander responses readily fit into current models of carcinogenesis,"
Lehnert said. "This makes this new area of radiobiological research so interesting and important. The bystander effect may or may not contribute to cancer, as yet we simply don't know its full
health implications. The confirmation of its existence and newly available information about its
causes, at least in cell culture systems, are already changing how we think about risk assessment."

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